Kentaro Sawada

Comparison of efficacy and toxicity of FOLFIRINOX and gemcitabine with nab-paclitaxel in unresectable pancreatic cancer

BACKGROUND Irinotecan, oxaliplatin and leucovorin-modulated fluorouracil (FOLFIRINOX) and the combination regimen of gemcitabine and nanoparticle albumin-bound paclitaxel (GnP) (nab-PTX) improve the prognosis of patients with metastatic pancreatic cancer. However, no study has compared the efficacy of the two regimens. We compared retrospectively the efficacy and safety of the two regimens in patients with unresectable pancreatic cancer. METHODS Thirty-eight patients with unresectable locally advanced or metastatic pancreatic cancer received FOLFIRINOX or GnP as first-line chemotherapy between December 2013 and September 2015. In the FOLFIRINOX group, patients received 85 mg/m2 oxaliplatin followed by 180 mg/m2 irinotecan and 200 mg/m2 L-leucovorin, and by 400 mg/m2 fluorouracil as a bolus and 2,400 mg/m2 fluorouracil as a 46-h continuous infusion every 14 days. In the GnP group, patients received 125 mg/m2 nab-PTX followed by 1 g/m2, and gemcitabine on days 1, 8 and 15, repeated every 28 days. RESULTS Response rate was 6.3% in the FOLFIRINOX group and 40.9% in the GnP group (P=0.025). Median progression-free survival (PFS) was 3.7 months [95% confidence interval (CI), 3.0-4.5] in the FOLFIRINOX group and 6.5 months (95% CI, 6.2-6.9 months) in the GnP group (P=0.031). Drug toxicity in the GnP group was less than in the FOLFIRINOX group. CONCLUSIONS Efficacy and safety of GnP compare favorably to those of FOLFIRINOX in patients with pancreatic cancer. Additional prospective trials are warranted.

Prognostic and Predictive Value of HER2 Amplification in Patients With Metastatic Colorectal Cancer

Micro‐Abstract: We evaluated the prognostic impact of human epidermal growth factor receptor 2 (HER2) amplification in metastatic colorectal cancer as well as the efficacy of anti–epidermal growth factor receptor (EGFR) therapy. HER2 amplification was as potentially prognostic for overall survival as RAS or BRAFV600E mutation as well as a potential negative predictive factor of anti‐EGFR therapy in metastatic colorectal cancer. Purpose: To evaluate a prognostic and predictive value of HER2 amplification in patients with metastatic colorectal cancer (mCRC). Patients and Methods: Patients with mCRC who underwent surgical resection of the primary tumor and who received best supportive care with or without palliative chemotherapy between 2005 and 2015 were included. HER2 immunohistochemistry was performed using formalin‐fixed, paraffin‐embedded primary tumor specimens. HER2 amplification was confirmed by fluorescence in‐situ hybridization. The RAS and BRAFV600E mutations were centrally assessed using a PCR‐based method. Patients were divided into 4 subgroups: R (RAS mutant), B (BRAFV600E mutant), H (wild‐type RAS/BRAF with HER2 amplification), and W (wild‐type RAS/BRAF without HER2 amplification). Overall survival (OS) and progression‐free survival of anti–epidermal growth factor receptor (EGFR) therapy were assessed. Results: Among 370 eligible patients, data of 359 were successfully analyzed. Fifteen tumors harbored HER2 amplifications, including 4 tumors with concomitant RAS mutation (group R). The number of patients in groups R, B, H, and W was 204, 13, 11, and 131, respectively. The median OS was 27.4 months, and the median follow‐up time was 63.2 months. The median OS for groups R, B, H, and W was 24.0, 14.2, 19.9, and 39.1 months, respectively. The number of patients who received anti‐EGFR therapy in groups R, B, H, and W was 17, 4, 5, and 49, respectively. Progression‐free survival of anti‐EGFR therapy was significantly shorter in groups R, B, and H than in group W. Conclusion: HER2 amplification was predictive of anti‐EGFR therapy response and appeared to be prognostic in mCRC patients.

The Clinical Landscape of Circulating Tumor DNA in Gastrointestinal Malignancies

Technologies for genomic analyses have revealed more details in cancer biology and have changed standard treatments for cancer, including the introduction of targeted gene-specific therapy. Currently, liquid biopsies are increasingly being utilized in clinical trials and research settings to analyze circulating tumor DNA (ctDNA) from peripheral blood. Several studies have shown the potential of ctDNA in the screening, prognostication, molecular profiling, and monitoring of gastrointestinal malignancies. Although limitations continue to exist in the use of ctDNA, such as method standardization, the sensitivity, concordance with tumor tissue, and regulatory issues, this field offers promising benefits for cancer treatment. A deeper understanding of tumor biology via ctDNA analyses and ctDNA-guided clinical trials will lead to the increasing use of ctDNA in clinical practice in the near future; this development will result in the improvement of outcomes among patients with gastrointestinal malignancies.

Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment (Edition 1.0)

In Japan, the social (medical) health‐care system is on the way to being developed to advance personalized medicine through the implementation of cancer genomic medicine, known as “cancer clinical sequencing,” which uses a next‐generation sequencer. However, no Japanese guidance for cancer genomic testing exists. Gene panel testing can be carried out to help determine patient treatment, confirm diagnosis, and evaluate prognostic predictions of patients with mainly solid cancers for whom no standard treatment is available. This guidance describes how to utilize gene panel testing according to the type of cancer: childhood cancer, rare cancer, carcinoma of unknown primary, and other cancers. The level of evidence classification for unified use in Japan is also detailed. This guidance establishes the basic principles of the quality control of specimens, requirements of medical institutions, informed consent, handling of data during the postanalysis stage, and treatment options based on the evidence level. In Japan, gene panel testing for cancer treatment and diagnosis is recommended to comply with this guidance. This is a collaborative work of the Japanese Society of Medical Oncology, Japan Society of Clinical Oncology, and the Japanese Cancer Association.

Feasibility Study of Bolus 5-Fluorouracil+L-Leucovorin as Salvage Line Chemotherapy for Oral Fluorouracil-Resistant Unresectable Gastric Cancer: Hokkaido Gastrointestinal Cancer Study Group Study HGCSG1502

In November 2015 we began a feasibility study of salvage line chemotherapy with 5-fluorouracil and l-leucovorin given in an intravenous bolus once weekly followed by a 2-week rest period within a 8-week cycle in patients with gastric cancer resistant to other chemotherapies. This study aims to assess the safety and efficacy of this treatment and determine whether the treatment has an adverse effect on patients’ quality of life. In total, 38 patients with chemotherapy-resistant advanced or recurrent gastric cancer will be recruited to this study. The primary end point is 8-week progression-free survival after the date of first treatment; the major secondary end points are progressionfree survival, overall survival, and quality of life assessed by European Organization for Research and Treatment of Cancer QLQ-C30 (quality of life score-30) and QLQ-STO22 (quality of life for gastric cancer patients) questionnaires. Based on the results of the study, we will conduct further trials to compare this treatment with best supportive care only.

Efficacy and Safety of Bolus 5-Fluorouracil and L-Leucovorin as Salvage Chemotherapy for Oral Fluoropyrimidine-Resistant Unresectable or Recurrent Gastric Cancer: A Single Center Experience

Purpose The International Organization for Standardization-5fluorouracil (FU) 10 trial found that bolus 5-FU and l-leucovorin was not inferior to S-1 in the treatment of gastric cancer (GC). Continuous 5-FU and the rapid injection of 5-FU have different anti-cancer effects. Thus, bolus 5-FU and l-leucovorin treatment might be useful for oral FU-resistant GC. Materials and Methods We retrospectively analyzed the medical records of all patients with S-1 or capecitabine-resistant, unresectable, or recurrent GC treated with bolus 5-FU and l-leucovorin between January 2010 and December 2015 at Hokkaido University Hospital. The bolus 5-FU and l-leucovorin regimen consisted of intravenous l-leucovorin (250 mg/m2/2 h) and bolus 5-FU (600 mg/m2) administered once weekly followed by a 2-week rest period; each cycle was repeated every 8 weeks. Results A total of 14 patients were identified. The disease control rate was 35.7%. The median progression-free survival was 1.6 months (95% confidence interval [CI], 1.3~2.0 months), and the median overall survival was 6.3 months (95% CI, 4.7~7.9 months). No patient died from treatment-related causes. The most common severe adverse event associated with bolus 5-FU and l-leucovorin was neutropenia, which occurred in 21.4% of patients. Conclusions Bolus 5-FU and l-leucovorin treatment might be useful for oral FU-resistant GC. We are planning a multi-center prospective phase II trial to evaluate the efficacy and safety of bolus 5-FU and l-leucovorin treatment for pre-treated unresectable or recurrent GC to confirm the results of this limited, retrospective study.

Observational cohort study of first-line bevacizumab with oxaliplatin or irinotecan and fluoropyrimidines in metastatic colorectal cancer: HGCSG0802—Analysis of early tumor shrinkage (ETS).

753 Background: It was reported that early tumor shrinkage (ETS) was associated with better overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC) receiving first line chemotherapy. We investigated association of ETS with progression-free survival (PFS) and OS in pts with mCRC treated with first-line bevacizumab (BV)-based chemotherapy (HGCSG0802). Methods: The objective of HGCSG0802 was to evaluate PFS, OS, response rate (RR), safety and so on. The key eligibility criteria were evaluable lesions, older than 20 years old, ECOG PS 0-2. This analysis evaluated the association of ETS at 8 weeks from the start of chemotherapy with pts characteristics, PFS and OS. To identify factors associated with ETS, if there were clinical variables with p < 0.2 in univariate analysis, we planned a multivariate analysis using the logistic regression model. To identify predictive and prognostic factors, a multivariate analysis was performed using Cox proportional hazard model with backward eliminat...

Updated analysis: Observational cohort study of first-line bevacizumab combined with chemotherapy in metastatic colorectal cancer (HGCSG0802)—Sub-group analysis by KRAS Exon2 status.

522 Background: A few reports have shown the efficacy of bevacizumab (BV) independent of the KRAS Exon2 mutational status (KRAS). We performed a sub-group analysis by KRAS from the HGCSG0802 observational cohort study that investigated 115 patients (pts) treated with 1st line BV for metastatic colorectal cancer (mCRC). Methods: The objective of HGCSG0802 was to evaluate progression-free survival (PFS), overall survival (OS), response rate (RR), and safety. The key eligibility criteria were with evaluable lesions, older than 20 years, ECOG PS 0-2. In this analysis, pts characteristics, RR and safety were compared using Fisher’s exact test. Univariate and multivariate analysis for PFS and OS were performed using patient characteristics. Survival analyses were performed with Kaplan-Meier method and Cox proportional hazards model. Results: Of 108 pts (the full analysis set), 99 pts were evaluable for KRAS. Sixty-two pts (62.6%) had KRAS wild-type (wt) and 37 pts (37.4%) had mutation (mt). The pts characterist...